Project Summary Human endogenous retrotransposable elements (HEREs) make up approximately 42% of the human genome. Included amongst these elements are the LTR associated human endogenous retrovirus insertions (HERVs), and the non-LTR associated long and short interspersed nuclear elements (LINE and SINE). The prevalence of HERV elements has resulted from the accumulation of past retroviral infectious agents that have entered the germline and established a truce with the host cell. LINE and SINE elements, which are not thought to have been derived from infectious precursors, have proliferated throughout the genome by a 'copy and paste' retrotransposition mechanism. Recent data have shown that these elements are under the cellular control of the innate resistance factors APOBEC3B, 3A, 3F and 3G. We have generated data that shows HIV-1 infection of primary CD4+ T cells and macrophages in vitro resulted in enhanced levels of HERE transcripts, and the accumulation of additional HERE genomic copies, indicating the induction of successfully completed retrotransposition events. HERE transcripts in the plasma were detected in individuals with acute/early HIV-1 infection not on antiretroviral drug treatment. These latter individuals had detectable ex vivo T cell responses to HERV antigens, and the magnitude of the anti-HERE response inversely correlated with HIV-1 plasma viral load. This grant proposes in one specific aim to determine whether the immune response generated to these elements can eliminate HIV-1 infected cells. We will determine the relationship between anti-HERE T cell response and HIV-1 plasma viral load, and how anti-HERE T cell clones recognize virus infected cells in vitro and if they can suppress HIV-1 viral replication in a viral inhibition assay. Elicitation of T cells against HEREs by vaccination would lead to T cell recognition of HIV-1 via both cross-reactivity between HEREs and HIV-1 and independent recognition of HERE antigens produced by HIV-1 infected cells. The work proposed in this grant aims to generate data for a novel vaccine strategy against HIV-1.